Amyotrophic lateral sclerosis (hereinafter, ALS) is a representative fatal neurodegenerative disease for which the establishment of effective therapy is strongly desired. In Japan, ALS has been designated as a specific intractable disease by the Ministry of Health, Labour and Welfare. The prevalence rate of ALS is regarded to be about 3 to 5 persons in a population of 100,000, and currently, it is believed that there are about 4,000 to 5,000 patients in Japan. In addition, ALS occurs after the middle age, which is the prime of one's life. Therefore, development of a novel therapy for ALS is extremely important.
From a historical standpoint, ALS is one disease entity described by Charcot and Joffroy in 1869 (Non-Patent Document 1). It is a progressive disease of unknown cause, in which both of the upper motor neuron and the lower motor neuron are generally impaired, and has been regarded as a motor neuron disease leading to death from paralysis of respiratory muscles (Non-Patent Document 2). Although it has been about 130 years since ALS was firstly reported, no effective therapy for the disease has been established. The effects of drugs based on neurotrophic factors, neuroprotective effects, caspase inhibition, copper chelating action, glutamate inhibitory action, and antioxidants have been investigated to discover the therapeutic agents for ALS. However, the only product currently marketed as a therapeutic agent for ALS is riluzole, which has glutamate inhibitory action as an agonist of glutamate receptors (Patent Document 1).
Antioxidants, namely, vitamin E which is a free radical scavenger, and allopurinol which is a xanthine oxidase inhibitor, are known to counteract the neurotoxin in cerebrospinal fluid from ALS patients in vitro (Non-Patent Document 3).
About 5 to 10% of ALS are familial amyotrophic lateral sclerosis (hereinafter, FALS) (Non-Patent Documents 4 and 5). As an etiological clue for ALS, in 1993, it was reported that about 20% of the FALS have copper/zinc superoxide dismutase (SOD1) gene mutation (Non-Patent Documents 2, 6 and 7). Based on this report, the transgenic mouse which expresses human mutated SOD1 gene at a high level has been developed (Non-Patent document 8). This transgenic mouse exhibits symptoms of motor paralysis due to motor neuron disorder in the same symptom as in human ALS, and the mouse eventually shows quadriplegia and a moribund state, and then exhibits respiratory muscle paralysis and dies. In addition, the mouse also exhibits histopathological findings of motor neuron disorder which are histopathologically identical to that of human. Therefore, this transgenic mouse is useful as an animal model for human ALS. Recently, it has been reported that arimoclomol, which is a hydroxylamine derivative with HSP (heat shock protein)-inducing action, leads to prolongation of life in the transgenic mouse, and thus being useful against ALS (Non-Patent Document 9).
[Patent Document 1] Japanese Patent No. 2713384
[Non-Patent Document 1] Charcot J M & Joffroy A. Arch Physiol (Paris) 1869; 2:744-760
[Non-Patent Document 2] Kato, et al. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. ISN Neuropath Press, 2003: pp. 350-368
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[Non-Patent Document 8] Gurney M E, et al. Science 1994; 264:1772-1775
[Non-Patent Document 9] Nature Medicine, 10:402-405, 2004